Breast cancer kills thousands of women annually. While surgical intervention has saved the lives of many women, radical and partial mastectomies often prove physically and emotionally debilitating. Indeed, surgery, even when combined with chemotherapy, may still expose the patient to the threat of possible recurrence.
A drug that promotes the prevention of breast cancer is desirable, and research efforts have been directed to the development of such drugs. For example, retinoic acid, a vitamin A metabolite, and certain retinoic acid analogues, appear to be necessary for the maintenance of normal epithelial tissue differentiation and can reverse the metaplastic condition of hamster tracheal in vitamin A deficient epithelial tissue. (Newton et al. Cancer Res. (1980) 40, 3413-3425). As a result, retinoic acid and certain amide analogues have been proposed as cancer chemopreventive agents, and display cancer preventive activity (Moon et al. Cancer Res. (1979) 39, 1339-1346). Similarly, retinoic acid analogues such as retinyl acetate, 13-cis-retinoic acid, glucuronide analogues of retinoic acid also display cancer preventive activity, including breast cancer preventative activity (Hill, D. L. et al. Ann. Rev. Nutrition (1992) 12, 161-181 and Mehta, R. G. et al. Oncology (1991) 48, 1505-1509).
However, a major impediment to developing retinoic acid and its closely related analogues, has been their relatively high toxicity (Biesalski, H. K. Toxicology (1989) 57, 117-161). Side effects such as teratogenicity, hepatotoxicity, scaly skin, hair loss and headaches have been observed as a result of the use of most of these compounds. Researchers have been pursuing the synthesis of retinoic acid analogues with increased potency and/or reduced toxicity for application as cancer preventative agents. It has been found that N-(4-hydroxyphenyl) retinamide (hereinafter "4-HPR") displays chemopreventive activity in breast cancer (Moon et al. Cancer Res. (1979) 39, 1339-1346). Indeed, 4-HPR when combined with calcium glucarate, synergistically exerts an increased breast cancer chemopreventive activity in carcinogen-induced rat mammary tumors (Abou-Issa, H. M. et al. Proc. Natl. Acad. Sci. USA (1988) 85, 4181-4184). However, the 4-HPR still displays significant cytotoxicity as shown in cultured human breast cancer cells (Bhatnagar, R. et al. Biochem. Pharmacol. (1991) 41, 1471-1477).
The glucuronide, N-(4-hydroxyphenyl)retinamide-O-glucuronide (hereinafter "4-HPR-O-glucuronide") has a greater antiproliferative activity and less toxicity in both MCF-7 human mammary cell tumor culture than the 4-HPR. (Bhatnagar, R. et al. Biochem. Pharmacol. (1991) 41, 1471-1477.)
However, the 4-HPR-O-glucuronide is unstable; it is hydrolyzed in acidic media and also by the enzyme .beta.-glucuronidase. The propensity to acid hydrolysis may limit the clinical usefulness of 4-HPR-O-glucuronide since oral administration of the drug may reduce the total available concentration of the active drug. Similarly, since .beta.-glucuronidase is present in virtually all mammalian cells, including the blood, liver and intestine, the in vivo half life is quite limited.
It is desirable to have stable chemopreventive drugs, for the prevention and treatment of breast cancer, which resist acid and .beta.-glucuronidase hydrolysis.